EP0562833A1 - Antimagengeschwür Pyridyloxyderivate, Verfahren zu deren Herstellung und ihre Verwendung - Google Patents

Antimagengeschwür Pyridyloxyderivate, Verfahren zu deren Herstellung und ihre Verwendung Download PDF

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EP0562833A1
EP0562833A1 EP93302221A EP93302221A EP0562833A1 EP 0562833 A1 EP0562833 A1 EP 0562833A1 EP 93302221 A EP93302221 A EP 93302221A EP 93302221 A EP93302221 A EP 93302221A EP 0562833 A1 EP0562833 A1 EP 0562833A1
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groups
group
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methyl
multiplet
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EP0562833B1 (de
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Hiroshi Fukumi
Mitsuo Sugiyama
Keiichi Tabata
Koichi Kojima
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Sankyo Co Ltd
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Sankyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a series of new pyridyloxy derivatives which have the ability to inhibit the secretion of gastric juices and which may thus be used for the treatment and prevention of ulcers.
  • the invention also provides methods and compositions using these new compounds for such treatment and prevention and processes for the preparation of these compounds.
  • Peptic ulcers are said to occur when there is an imbalance between factors which attack the gastrointestinal mucosa and factors which defend the gastrointestinal mucosa.
  • the gastric juice is among the attacking factors. Accordingly, if its secretion could be inhibited, this would be useful for the prevention and therapy of ulcers.
  • anticholinergic agents and histamine-H2 receptor antagonists have been widely used clinically and have had considerable success, although they are not free from disadvantages.
  • anticholinergic agents have exhibited a range of side effects, including inhibition of movement of the gastrointestinal tract, thirst, mydriasis and inhibition of sweating.
  • histamine-H2 receptor antagonists also have undesirable side effects on the central nervous system, and may also have an antagonistic effect on androgens.
  • histamine-H2 receptor antagonists may weaken mucosal protecting factors after long-term administration, and recurrence of ulcers after withdrawal of these drugs has also been observed. Since recurrence is thought to be caused by a decrease in the protecting factors, a drug having the ability both to inhibit gastric juice secretion and to potentiate protecting factor activity would be highly desirable.
  • a number of compounds having anti-ulcer activity and similar structures to the pyridyloxy derivatives of the present invention is known. Examples include Compound A (disclosed, for example, in European Patent Publication No. 404 949 or WO90/00544), Compound B (disclosed, for example, in Japanese Patent Kokai Application No. Hei-1-193247, Japanese Patent Kokai Application No. Sho-63-225371 and European Patent Publication No. 282 077) and Compound C (disclosed, for example, in Japanese Patent Kokai Application No. Hei-4-257581):
  • Compound C was disclosed after the priority dates hereof.
  • the compounds of the present invention surprisingly have substantially better activities than these structurally similar compounds and have a combination of gastric juice secretion inhibitory, anti-ulcer and defence factor potentiating activities which these prior compounds do not possess.
  • the compounds of the present invention are those compounds of formula (I) : wherein: R1 represents a cyclic amino group having from 3 to 7 ring atoms, of which from 1 to 3 are nitrogen atoms, 0 or 1 is an oxygen atom or a sulphur atom, and the remainder are carbon atoms, or a dialkylamino group in which each alkyl group is independently selected from alkyl groups having from 1 to 4 carbon atoms; R2 represents a group of formula -NHCHR3R4, wherein R3 and R4 are independently selected from alkyl groups having from 1 to 6 carbon atoms, aryl groups as defined below and aralkyl groups as defined below, or R3 and R4, together with the carbon atom to which they are attached, represent a cycloalkyl group having from 3 to 8 ring carbon atoms, which group is unsubstituted or is substituted by at least one substituent selected from substituents ⁇ , an aromatic heterocyclic group having 5 ring atoms,
  • the invention also provides a pharmaceutical composition for the treatment and prophylaxis of ulcerous conditions, which comprises an anti-ulcer compound in admixture with a pharmaceutically acceptable carrier or diluent, wherein the anti-ulcer compound is selected from compounds of formula (I) and pharmaceutically acceptable salts thereof.
  • the invention still further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a pharmaceutical.
  • the present invention also provides processes for preparing these compounds, which are described in greater detail hereafter.
  • R1 represents a cyclic amino group
  • this has from 3 to 7 ring atoms, including at least one nitrogen atom.
  • the group is attached to the methylene group forming part of the remainder of the molecule by means of a nitrogen atom.
  • the group preferably has a single nitrogen atom, the remainder of the ring atoms being carbon.
  • Examples of such groups include the 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino and 1-hexahydroazepinyl groups. Of these we prefer the 1-pyrrolidinyl and piperidino groups, more preferably the piperidino group.
  • R1 represents a dialkylamino group or substituent ⁇ , ⁇ , ⁇ or ⁇ represents an alkyl group
  • this alkyl group may be a straight or branched chain alkyl group having from 1 to 4 carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups, preferably the methyl, ethyl, propyl, isopropyl, butyl and sec-butyl groups, and most preferably the methyl or ethyl group.
  • dialkylamino group represented by R1 the two alkyl groups may be the same or different, although they are preferably the same.
  • Specific examples of dialkylamino groups include the dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino, methylethylamino and methylpropylamino, of which we prefer the dimethylamino, diethylamino and dipropylamino groups, especially the dimethylamino group.
  • R2 represents a group of formula -NHCHR3R4, and R3 and/or R4 represents an alkyl group having from 1 to 6 carbon atoms
  • this may be a straight or branched chain group having from 1 to 6, preferably from 1 to 4, carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohex
  • R2 represents a group of formula -NHCHR3R4, and R3 and/or R4 represents an aryl group
  • this has from 6 to 10, preferably 6 or 10, ring carbon atoms and may be unsubstituted or it may be substituted by one or more of substituents ⁇ , defined above and exemplified below.
  • substituents ⁇ defined above and exemplified below.
  • Specific examples of the unsubstituted aryl groups include the phenyl and naphthyl (1- or 2- naphthyl) groups, of which the phenyl group is preferred.
  • the aryl ring may optionally have one or more substituents (preferably from 1 to 3 substituents, and more preferably 1 substituent).
  • substituents are alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, and halogen atoms (such as the fluorine, chlorine, bromine or iodine atoms).
  • Preferred substituents are the methyl group, the methoxy group, the fluorine atom and the chlorine atom.
  • the substituents are, in the case of substituted phenyl groups, preferably on the 4-position. Examples of preferred substituted phenyl groups include the 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl and 4-fluorophenyl groups.
  • R2 represents a group of formula -NHCHR3R4, and R3 and/or R4 represents an aralkyl group
  • the aryl part may be as exemplified above and the alkyl part may be any one of those alkyl groups having from 1 to 4 carbon atoms exemplified above.
  • the aryl and alkyl parts of the aralkyl group together have from 7 to 11 carbon atoms.
  • the aryl part of the aralkyl group may be substituted or unsubstituted, and, if substituted, the substituents are selected from substituents ⁇ defined above and exemplified below. However, the group is preferably unsubstituted.
  • aralkyl groups examples include the benzyl, phenethyl, 1-phenylethyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl and 1- and 2- naphthylmethyl groups, of which the benzyl, phenethyl and 1- and 2- naphthylmethyl groups are preferred, the benzyl group being most preferred.
  • R2 represents a group of formula -NHCHR3R4, and R3 and R4, together with the carbon atom to which they are attached, represent a cycloalkyl group, this has from 3 to 8 ring carbon atoms, and examples include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, of which the cyclopropyl, cyclobutyl and cyclopentyl groups are preferred, and the cyclopropyl and cyclobutyl groups are most preferred.
  • the cycloalkyl ring may be substituted or unsubstituted, and, if substituted, it preferably has from 1 to 3, more preferably 1, substituents selected from substituents ⁇ . Examples of such substituents are given in more detail below, but the preferred substituents are alkyl groups having from 1 to 4 carbon atoms and alkoxy groups having from 1 to 4 carbon atoms. Of these, we prefer the methyl or ethyl group, but the cycloalkyl group is preferably unsubstituted.
  • R2 represents an aromatic heterocyclic group
  • this has 5 ring atoms, of which from 1 to 3 are hetero-atoms selected from oxygen, nitrogen and sulphur atoms.
  • this may be any of the oxygen, nitrogen and sulphur atoms.
  • there are two or three hetero-atoms we prefer that all three or two should be nitrogen atoms and none or one should be an oxygen or sulphur atom.
  • Examples of such groups include the furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-thiadiazolyl, and 1,2,3- or 1,2,4-triazolyl groups.
  • the furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl and 1,2,3-thiadiazolyl groups are preferred, and the thienyl, thiazolyl, pyrrolyl, pyrazolyl and 1,2,3-thiadiazolyl groups are more preferred.
  • substituents ⁇ may be selected from substituents ⁇ , defined above and exemplified below. There is no particular limitation on the number of such substituents, except that the number of substitutable positions on 5-membered aromatic heterocyclic groups is 4, and from 1 to 4 such substituents are possible, from 1 to 3 being preferred and 1 or 2 being most preferred.
  • substituents ⁇ include: alkyl groups having from 1 to 4 carbon atoms, as exemplified above; alkoxy groups having from 1 to 4 carbon atoms, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups, of which the methoxy and ethoxy groups are preferred; hydroxy groups; halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms, of which the fluorine and chlorine atoms are preferred; amino groups; monoalkylamino groups in which the alkyl part has from 1 to 4 carbon atoms, such as the methylamino, ethylamino, propylamino, isopropylamino, butylamino and isobutylamino groups, preferably the methylamino and ethylamino groups; dialkylamino groups in which each alkyl part is independently selected from alkyl groups having from 1 to 4 carbon atom
  • substituents ⁇ are straight or branched chain alkyl groups having from 1 to 4 carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups, preferably the methyl, ethyl, propyl, isopropyl, butyl and sec-butyl groups, and most preferably the methyl or ethyl group.
  • R5 represents a substituted alkyl group
  • the alkyl moiety may be a straight or branched chain alkyl group having from 1 to 4 carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups, preferably the methyl, ethyl, propyl, isopropyl, butyl and sec-butyl groups, more preferably the ethyl or propyl group having a substituent at the 2-position, and most preferably the ethyl group having a substituent at the 2-position.
  • the group is substituted by at least one, and preferably from 1 to 3, more preferably 1, substituent selected from substituents ⁇ .
  • substituents ⁇ include: hydroxy groups; alkanoyloxy groups having from 1 to 5 carbon atoms, such as the formoxy, acetoxy, propionyloxy, butyryloxy, valeryloxy and isovaleryloxy groups, preferably the acetoxy or propionyloxy group; substituted alkanoyloxy groups which have from 2 to 5 carbon atoms and which are substituted by at least one substituent selected from substituents ⁇ , such as the acetoxy, propionyl- oxy, butyryloxy, valeryloxy and isovaleryloxy groups, preferably the acetoxy or propionyloxy group;
  • substituents ⁇ are: carboxy groups; alkoxycarbonyl groups in which the alkoxy part has from 1 to 4 carbon atoms, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl groups, of which the methoxy
  • R5 represents an aromatic heterocyclic group
  • this has 5 or 6 ring atoms, of which from 1 to 4 are hetero-atoms selected from oxygen, nitrogen and sulphur atoms.
  • this may be any of the oxygen, nitrogen and sulphur atoms.
  • 0 or 1 is an oxygen or sulphur atom and, where there are no oxygen or sulphur atoms, 1, 2, 3 or 4 are nitrogen atoms, or, where there is 1 oxygen or sulphur atom, 0, 1, 2 or 3 are nitrogen atoms.
  • Examples of such groups include the furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-thiadiazolyl, 1,2,3- or 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and 1,2,3-, 1,2,4- or 1,3,5-triazinyl groups.
  • imidazolyl 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl and pyrimidinyl groups, more preferably the 1,3,4-oxadiazolyl, 1,2,4-triazolyl, tetrazolyl and pyrimidinyl groups and most preferably the 1,3,4-oxadiazolyl, 1,2,4-triazolyl and pyrimidinyl groups.
  • Such groups may be unsubstituted or they may have one or more (preferably from 1 to 3) substituents selected from substituents ⁇ , in the case of substituents on carbon atoms, or substituents ⁇ , in the case of substituents on nitrogen atoms. Examples of substituents ⁇ have been given above.
  • substituents ⁇ are as follows: alkyl groups having from 1 to 4 carbon atoms, such as those exemplified above in relation to substituents ⁇ ; and hydroxyalkyl groups having from 2 to 4 carbon atoms, such as the 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl and 4-hydroxybutyl groups; preferably a 2-hydroxyethyl or 3-hydroxypropyl group.
  • B can represent an alkylene or alkylidene group having from 1 to 6 carbon atoms.
  • Examples include the methylene, ethylene, trimethylene, propylene, tetramethylene, 2-methyltrimethylene, pentamethylene and hexamethylene groups. Of these, we prefer the methylene, ethylene or trimethylene group, more preferably a methylene or trimethylene group.
  • n is 0 or 1, and most preferably m is 0.
  • R2 preferred optionally substituted 5-membered aromatic heterocyclic groups containing from 1 to 3 hetero-atoms selected from oxygen, nitrogen and sulphur atoms, which may be represented by R2 include the 2-furyl, 3-furyl, 3-methyl-2-furyl, 4-methyl-2-furyl, 5-methyl- 2-furyl, 2-methyl-3-furyl, 4-methyl-3-furyl, 5-methyl- 3-furyl, 5-chloro-2-furyl, 5-chloro-3-furyl, 3-amino-2- furyl, 5-amino-2-furyl, 3-acetamido-2-furyl, 5-acetamido-2-furyl, 5-phenyl-2-furyl, 5-(4-methylphenyl)-2-furyl, 5-(4-chlorophenyl)-2-furyl, 2,4-dimethyl-3-furyl, 2,5-dimethyl-3-furyl, 3-methyl-5-amino-2-furyl, 2-thienyl
  • Examples of more preferred such groups include: the 2-furyl, 3-furyl, 3-methyl-2-furyl, 4-methyl-2-furyl, 5-methyl-2-furyl, 2-methyl-3-furyl, 4-methyl-3-furyl, 5-methyl-3-furyl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl, 2-methyl-3-thienyl, 4-methyl-3-thienyl, 5-methyl-3-thienyl, 5-chloro-2-thienyl, 5-chloro-3-thienyl, 3-amino-2-thienyl, 5-amino-2-thienyl, 2-amino-3-thienyl, 4-amino-3-thienyl, 3-acetamido-2-thienyl, 5-acetamido-2-thienyl, 2-acetamido-3-thienyl, 4-acetamido-3-thienyl, 2-pyrrol
  • Examples of still more preferred such groups include: the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl, 2-methyl-3-thienyl, 4-methyl-3-thienyl, 5-methyl-3-thienyl, 5-chloro-2-thienyl, 5-chloro-3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1-methyl-2-pyrrolyl, 3-methyl-2-pyrrolyl, 4-methyl-2-pyrrolyl, 5-methyl-2-pyrrolyl, 1-methyl-3-pyrrolyl, 2-methyl-3-pyrrolyl, 4-methyl-3-pyrrolyl, 5-methyl-3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-methyl-4-thiazoly
  • R2 examples of the most preferred such groups which may be represented by R2 include: the 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 5-chloro-3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1-methyl-2-pyrrolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-methyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 5-methyl-3-pyrazolyl, 3-amino-4-pyrazolyl, 1,2,3-thiadiazol-4-yl groups and 1,2,3-thiadiazol-5-yl groups.
  • optionally substituted 5- or 6-membered aromatic heterocyclic groups having from 1 to 4 hetero-atoms selected from oxygen, nitrogen and sulphur atoms which may be represented by R5 include: the 2-furyl, 3-furyl, 3-methyl-2-furyl, 4-methyl-2-furyl, 5-methyl-2-furyl, 2-methyl-3-furyl, 4-methyl-3-furyl, 5-methyl-3-furyl, 5-chloro-2-furyl, 5-chloro-3-furyl, 3-amino-2-furyl, 5-amino-2-furyl, 3-acetamido-2-furyl, 5-acetamido-2- furyl, 5-phenyl-2-furyl, 5-(4-methylphenyl)-2-furyl, 5-(4-chlorophenyl)-2-furyl, 2,4-dimethyl-3-furyl, 2,5-dimethyl-3-furyl, 3-methyl-5-amino-2-furyl, 2-thieny
  • Examples of preferred such groups include: the 2-furyl, 3-furyl, 3-methyl-2-furyl, 4-methyl-2-furyl, 5-methyl-2-furyl, 2-methyl-3-furyl, 4-methyl-3-furyl, 5-methyl-3-furyl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl, 2-methyl-3-thienyl, 4-methyl-3-thienyl, 5-methyl-3-thienyl, 5-ethyl-2-thienyl, 4-methoxy-2-thienyl, 4-methoxy-3-thienyl, 3-amino-2-thienyl, 5-amino-2-thienyl, 2-amino-3-thienyl, 4-amino-3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1-methyl-2-pyrrolyl, 3-methyl-2-pyrrolyl, 4-methyl-2-pyrrolyl, 5-methyl-2-pyr
  • Examples of more preferred such groups include: the 2-imidazolyl, 4-imidazolyl, 1-methyl-2-imidazolyl, 5-methyl-2-imidazolyl, 1-methyl-4-imidazolyl, 2-methyl-4-imidazolyl, 5-methyl-4-imidazolyl, 4-chloro-2-imidazolyl, 2-chloro-4-imidazolyl, 5-chloro-4-imidazolyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 5-chloro-1,3,4-oxadiazol-2-yl, 5-amino-1,3,4-oxadiazol-2-yl, 5-acetamido-1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-ethyl-1,3,4-thiadiazol-2
  • Examples of still more preferred such groups include: the 2-imidazolyl, 4-imidazolyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1-methyl-1,2,4-triazol-3-yl, 1-methyl-1,2,4-triazol-5-yl, 5-methyl-1,2,4-triazol-3-yl, tetrazol-5-yl, 1-methyltetrazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 2-methyl-4-pyridyl, 3-methyl-4-pyridyl, 3-amin
  • Examples of the most preferred such groups include: the 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1-methyl-1,2,4-triazol-3-yl, 1-methyl-1,2,4-triazol-5-yl, 5-methyl-1,2,4-triazol-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 4-methyl-2-pyrimidinyl, 5-methyl-2-pyrimidinyl, 2-methyl-4-pyrimidinyl, 5-methyl-4-pyrimidinyl and 6-methyl-4-pyrimidinyl groups.
  • the compounds of the present invention can form salts. Where the compound contains a carboxy group, it can form a salt with a cation.
  • salts include: salts with an alkali metal, such as sodium, potassium or lithium; salts with an alkaline earth metal, such as barium or calcium; salts with another metal, such as magnesium or aluminium; ammonium salts; organic base salts, such as a salt with triethylamine, diisopropylamine, cyclohexylamine or dicyclohexylamine; and salts with a basic amino acid, such as lysine or arginine.
  • the compounds of the present invention necessarily contain basic groups in their molecules, they can form acid addition salts.
  • Such acid addition salts include: salts with mineral acids, especially hydrohalic acids (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid), nitric acid, perchloric acid, carbonic acid, sulphuric acid or phosphoric acid; salts with lower alkylsulphonic acids, such as methanesulphonic acid, trifluoromethanesulphonic acid or ethanesulphonic acid; salts with arylsulphonic acids, such as benzenesulphonic acid or p -toluenesulphonic acid; salts with organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid, citric acid or 2-(4-hydroxybenzoyl)benzoic acid; and salts with amino acids, such as glutamic acid,
  • the compounds of the present invention may contain several asymmetric carbon atoms in their molecules, and can thus form optical isomers. Although these are all represented herein by a single molecular formula, the present invention includes both the individual, isolated isomers and mixtures, including racemates thereof. Where stereospecific synthesis techniques are employed or optically active compounds are employed as starting materials, individual isomers may be prepared directly; on the other hand, if a mixture of isomers is prepared, the individual isomers may be obtained by conventional resolution techniques.
  • R1 represents a cyclic amino group having from 3 to 7 ring atoms, of which 1 is a nitrogen atom and the remainder are carbon atoms, or said dialkylamino group, more preferably those wherein R1 represents a cyclic amino group having 5 or 6 ring atoms, of which 1 is a nitrogen atom and the remainder are carbon atoms, or said dialkylamino group, especially those wherein R1 represents a 1-pyrrolidinyl, piperidino, dimethylamino or diethylamino group.
  • R2 represents a group of formula -NHCHR3R4, wherein R3 and R4 are independently selected from: alkyl groups having from 1 to 4 carbon atoms, phenyl groups which are unsubstituted or have at least one substituent selected from substituents ⁇ , defined above, and benzyl and phenethyl groups; R3 and R4, together with the carbon atom to which they are attached, represent a cycloalkyl group having from 3 to 6 ring carbon atoms,
  • R2 represents an aromatic heterocyclic group having 5 ring atoms, of which 1 is a hetero-atom selected from nitrogen, oxygen and sulphur hetero-atoms, there are 0, 1 or 2 additional nitrogen hetero-atoms, and the remaining ring atoms are carbon atoms, said group being unsubstituted or having at least one substituent selected, in the case of substituents on carbon atoms, from substituents ⁇ and, in the case of substituents on nitrogen atoms, from substituents ⁇ , as defined above, and particularly those wherein said aromatic heterocyclic group is selected from furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl and thiadiazolyl groups, which are unsubstituted or are substituted as defined above.
  • a further alternative preferred class of compounds of the present invention are those wherein R2 represents a group of formula -B-S(O) m -R5, wherein: B represents an alkylene or alkylidene group having from 1 to 3 carbon atoms; m is 0, 1 or 2; and R5 represents: a substituted alkyl group which has from 2 to 4 carbon atoms and which is substituted at its 2-position by at least one substituent selected from substituents ⁇ ; or an aromatic heterocyclic group which has 5 or 6 ring atoms of which 1 is a hetero-atom selected from nitrogen, oxygen and sulphur hetero-atoms, there are 0, 1, 2 or 3 additional nitrogen hetero-atoms, and the remaining ring atoms are carbon atoms, said group being unsubstituted or having at least one substituent selected, in the case of substituents on carbon atoms, from substituents ⁇ and, in the case of substituents on nitrogen atoms, from substituents ⁇ , as defined above.
  • R1 represents a 1-pyrrolidinyl, piperidino, dimethylamino or diethylamino group
  • R2 represents a group of formula -NHCHR3R4, wherein R3 and R4 are independently selected from alkyl groups having from 1 to 4 carbon atoms, benzyl groups, phenethyl groups and phenyl groups which are unsubstituted or which are substituted by at least one substituent selected from methyl, methoxy, fluorine atoms and chlorine atoms, or R3 and R4, together with the carbon atom to which they are attached, represent a cycloalkyl group having from 3 to 6 ring carbon atoms, a furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl or thiadiazolyl group, which is unsubstituted or is substitute
  • Still more preferred compounds of the present invention are those compounds of formula (I) and salts thereof, wherein: R1 represents a 1-pyrrolidinyl or piperidino group; R2 represents a group of formula -NHCHR3R4, wherein R3 and R4 are independently selected from methyl, ethyl, phenyl and benzyl groups, or R3 and R4, together with the carbon atom to which they are attached, represent a cycloalkyl group having from 3 to 5 ring carbon atoms, a furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl or 1,2,3-thiadiazolyl group, which is unsubstituted or is substituted by at least one substituent selected, in the case of substituents on carbon atoms, from substituents ⁇ 2 and, in the case of substituents on nitrogen atoms, from methyl and ethyl groups, or a group
  • R1 represents a piperidino group
  • R2 represents a group of formula -NHCHR3R4, wherein R3 and R4 are independently selected from methyl, ethyl, phenyl and benzyl groups, or R3 and R4, together with the carbon atom to which they are attached, represent a cycloalkyl group having 3 or 4 ring carbon atoms, a thienyl, pyrrolyl, thiazolyl, pyrazolyl or 1,2,3-thiadiazolyl group, which is unsubstituted or is substituted by at least one substituent selected, in the case of substituents on carbon atoms, from substituents ⁇ 4 and, in the case of substituents on nitrogen atoms, from methyl groups, or a group of formula -B-S(O) m -R5, wherein B represents a methylene group and R5 represents: a
  • R1 represents a piperidino group
  • Examples of specific preferred compounds of the present invention are those compounds of formula (I-1), in which the substituents are as defined in Table 1, and those compounds of formula (I-1), in which the substituents are as defined in Tables 2 and 3.
  • More preferred compounds are Compounds No. 1-46, 1-116, 1-137, 1-591, 1-612, 1-974, 1-1019, 2-2, 2-4, 2-5, 2-6, 2-7, 2-9, 2-10, 2-12, 2-20, 2-27, 2-28, 2-209, 2-211, 2-212, 2-216, 2-217, 2-218, 2-390, 2-392, 2-1147, 2-1148, 3-118, 3-238 and 3-579.
  • the compounds of the present invention may be prepared by a variety of methods well known in the art for the preparation of compounds of this type. For example, they may be prepared by the following Reactions A to G:
  • R1, R2, R3, R4, R5, A, B and m are as defined above;
  • R 2a represents any of the groups defined above for R2, except the groups of formula -NHCHR3R4 (wherein R3 and R4 are as defined above) and provided that any hydroxy group in the group represented by R2 is protected;
  • R 2b represents any of the groups defined above for R2, except the groups of formula -NHCHR3R4 (wherein R3 and R4 are as defined above);
  • R 5a represents a hydroxyalkyl group having from 2 to 4 carbon atoms (with the proviso that the group must include a moiety having the formula -CH2OH);
  • R6 represents an alkyl group having from 1 to 3 carbon atoms and substituted with a carboxy or alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkoxy moiety;
  • X represents a halogen atom, preferably a chlorine, bromine or iodine atom;
  • Y represents
  • hydroxy-protecting group there is no particular limitation upon the nature of this group, and any such group well known in the field of organic chemistry may equally be used here.
  • Typical examples of such groups include: cyclic ether groups, such as the tetrahydropyranyl, tetrahydrofuranyl and tetrahydrothiopyranyl groups; tri(C1-C4alkyl)silyl or di(C1-C4alkyl)arylsilyl groups, such as the trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and methyldiphenylsilyl groups; methyl groups substituted with a methoxy, methylthio or trihaloethoxy group, such as the methoxymethyl, methylthiomethyl and 2,2,2-trichloroethoxymethyl groups; and aralkyl groups, such as the benzyl and diphenylmethyl groups.
  • cyclic ether groups particularly a tetrahydropyranyl group
  • substituted silyl groups particularly a trimethylsilyl or t-butyldimethylsilyl group
  • methoxymethyl group we particularly prefer the cyclic ether groups (particularly a tetrahydropyranyl group), the substituted silyl groups (particularly a trimethylsilyl or t-butyldimethylsilyl group) and the methoxymethyl group.
  • a compound of formula (Ia) i.e. a compound of formula (I) in which R2 represents a group of formula -NHCHR3R4 (wherein R3 and R4 are as defined above) is prepared by reacting a compound of formula (II) with a compound of formula (III) in the presence of carbonyldiimidazole in an inert solvent.
  • the reaction is normally and preferably effected in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, diethylformamide or dimethylacetamide; nitriles, such as acetonitrile; and sulphoxides, such as dimethyl sulphoxide. Of these, we prefer the halogenated hydrocarbons.
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform
  • ethers such as diethyl ether, tetrahydrofuran or dioxane
  • amides such as dimethylform
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20°C to 100°C (more preferably from 0°C to 50°C).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 10 hours (more preferably from 1 to 5 hours) will usually suffice.
  • the desired compound can be recovered from the reaction mixture by conventional means.
  • one such recovery method comprises: distilling off the solvent from the reaction mixture or pouring the reaction mixture into water; extracting the mixture with a water-immiscible organic solvent; and distilling off the organic solvent, to leave the desired product as a residue.
  • the resulting product can be further purified by conventional means, such as recrystallisation, reprecipitation or the various chromatography techniques, notably column chromatography.
  • Reaction B comprises another method for preparing a compound of formula (Ia).
  • a compound of formula (Ia) is prepared by reacting a compound of formula (II) with a compound of formula (IV) in an inert solvent.
  • the reaction is normally and preferably effected in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol or isopropanol; and nitriles, such as acetonitrile.
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform
  • ethers such as diethyl ether, tetrahydrofuran or dioxane
  • alcohols such as methanol, ethanol or isopropanol
  • nitriles such as acetonitrile.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20°C to 100°C (more preferably from 0°C to 50°C).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 10 hours (more preferably from 1 to 5 hours) will usually suffice.
  • the desired compound can be recovered from the reaction mixture by conventional means.
  • one such recovery method comprises: distilling off the solvent from the reaction mixture or pouring the reaction mixture into water; extracting the mixture with a water-immiscible organic solvent; and distilling off the organic solvent, to leave the desired product as a residue.
  • the resulting product can be further purified by conventional means, such as recrystallisation, reprecipitation or the various chromatography techniques, notably column chromatography.
  • a compound of formula (Ib) that is a compound of formula (I) wherein R2 represents R 2b (R 2b is as defined above) is prepared by reacting an amine derivative of formula (II) with a carboxylic acid compound of formula (V) or with a reactive derivative of the carboxylic acid, and, if desired, removing any hydroxy-protecting group.
  • reaction of the amine of formula (II) with the carboxylic acid of formula (V) may be carried out in the presence or absence of a base and preferably in the presence of a condensing agent and of in an inert solvent.
  • condensing agent used for the reaction there is no particular limitation upon the nature of the condensing agent used for the reaction, and any reagent capable of producing an amide bond from a carboxylic acid and an amine may be used.
  • the preferred condensing agents include: dicyclohexylcarbodiimide (DCC); diethyl cyanophosphonate (DEPC); carbonyldiimidazole; diphenylphosphoryl azide (DPPA); 1-hydroxybenzotriazole in admixture with dicyclohexylcarbodiimide; or diethyl azodicarboxylate in admixture with triphenyl phosphine, Of these, we prefer either 1-hydroxybenzotriazole in admixture with dicyclohexylcarbodiimide or diethyl cyanophosphonate.
  • Examples of preferred bases which may be used include organic amines, such as trimethylamine, triethylamine, pyridine, dimethylaniline, N -methylmorpholine or 4-( N , N -dimethylamino)pyridine. Of these, we prefer triethylamine or N -methylmorpholine.
  • the reaction is normally and preferably effected in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; esters, such as ethyl acetate or propyl acetate; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and nitriles, such as acetonitrile.
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform
  • ethers such as diethyl ether, tetrahydrofuran or dioxane
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -10°C to 50°C (more preferably from 0°C to 30°C).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 24 hours (more preferably from 1 to 15 hours) will usually suffice.
  • the compound of formula (Ib) can be prepared by converting a carboxylic acid of formula (V) to a reactive derivative thereof, and reacting an amine of formula (II) with the reactive derivative.
  • Examples of reactive derivatives of the carboxylic acid compound include: acid halides, such as the acid chloride or acid bromide; acid azides; reactive esters, such as esters with N -hydroxybenzotriazole or N -hydroxysuccinimide; acid anhydrides of the carboxylic acid used; and mixed acid anhydrides comprising monoalkyl carbonates in which the alkyl group has from 1 to 4 carbon atoms (such as monomethyl carbonate, monoethyl carbonate or monoisobutyl carbonate) or monoaryl carbonates (such as monophenyl carbonate or monotolyl carbonate).
  • acid halides such as the acid chloride or acid bromide
  • acid azides reactive esters, such as esters with N -hydroxybenzotriazole or N -hydroxysuccinimide
  • acid anhydrides of the carboxylic acid used and mixed acid anhydrides comprising monoalkyl carbonates in which the alkyl group has from 1 to 4 carbon atoms (such as monomethyl carbonate
  • the reactive derivative of the carboxylic acid can be prepared by conventional means.
  • they may be prepared by reacting a carboxylic acid of formula (V) with an appropriate halide (for example, thionyl chloride, thionyl bromide, acid chloride or acid bromide of the desired carboxylic acid, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, phenyl chloroformate or tolyl chloroformate) in an inert solvent (for example, methylene chloride, benzene or tetrahydrofuran) and, if necessary, in the presence of a base (for example, pyridine, triethylamine or dimethylaniline) in the temperature range from 20°C to 100°C for a period of from 1 to 20 hours.
  • an appropriate halide for example, thionyl chloride, thionyl bromide, acid chloride or acid bromide of the desired carboxylic acid, methyl
  • reactive derivatives such as the acid amide or the reactive ester
  • an appropriate compound for example, hydrogen azide, N -hydroxybenzotriazole or N -hydroxysuccinimide
  • Reaction C for producing an amide bond using a carboxylic acid of formula (V) and an amine of formula (II).
  • the reaction of the amine of formula (II) and the reactive derivative of the carboxylic acid of formula (V) is preferably carried out in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; and esters, such as ethyl acetate.
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform
  • ethers such as diethyl ether, tetrahydrofuran or dioxane
  • esters such as ethyl acetate.
  • aromatic hydrocarbons or ethers we prefer the aromatic hydrocarbons or ethers.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -10°C to 50°C (more preferably from 0°C to 25°C).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 20 hours (more preferably from 30 minutes to 10 hours) will usually suffice.
  • reaction employed to remove the hydroxy-protecting group will, of course, vary depending upon the nature of the protecting group, but its removal may be achieved by conventional means well known in the field of organic chemistry.
  • the protecting group is a silyl group
  • it can be removed by reacting the corresponding compound with a base (for example, an alkali metal carbonate, such as sodium carbonate or potassium carbonate), an acid (for example, a mineral acid, such as hydrochloric acid or sulphuric acid, or an organic carboxylic acid, such as acetic acid or citric acid) or a fluoride (for example, an ammonium fluoride compound, such as tributylammonium fluoride) in an inert solvent.
  • a base for example, an alkali metal carbonate, such as sodium carbonate or potassium carbonate
  • an acid for example, a mineral acid, such as hydrochloric acid or sulphuric acid, or an organic carboxylic acid, such as acetic acid or citric acid
  • a fluoride for example, an ammonium fluoride compound, such as tributylammonium fluoride
  • the reaction is normally and preferably effected in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; and alcohols, such as methanol or ethanol. Of these, we prefer the alcohols.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20°C to 50°C (preferably from 0°C to 30°C).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 2 hours (more preferably from 20 minutes to 1 hour) will usually suffice.
  • the protecting group is a cyclic ether or a substituted methyl group
  • it can be removed by reacting the corresponding compound with an acid in an inert solvent.
  • acids which may be used for this reaction include: mineral acids, such as hydrochloric acid, hydrobromic acid or sulphuric acid; and organic sulphonic acids, such as methanesulphonic acid, benzenesulphonic acid or toluenesulphonic acid. Of these, we prefer hydrochloric acid or toluenesulphonic acid.
  • the reaction is normally and preferably effected in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol or ethanol; esters, such as ethyl acetate or propyl acetate; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and nitriles, such as acetonitrile. Of these, we prefer the halogenated hydrocarbons or esters.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20°C to 100°C (more preferably from 20°C to 70°C).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 15 minutes to 5 hours (more preferably from 30 minutes to 2 hours) will usually suffice.
  • the protecting group is an aralkyl group
  • it can be removed by reacting the corresponding compound with hydrogen in an inert solvent in the presence of a catalyst for reduction.
  • catalysts which may be used for reduction include: platinum oxide, platinum black, palladium-on-charcoal, and rhodium-on-charcoal. Of these, we prefer palladium-on-charcoal.
  • the hydrogen pressure used is normally in the range of from atmospheric pressure to 3 atmospheres pressure.
  • the reaction is normally and preferably effected in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol or ethanol; esters, such as ethyl acetate or propyl acetate; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and nitriles, such as acetonitrile. Of these, we prefer the alcohols.
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform
  • ethers such as diethy
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20°C to 100°C (more preferably from 10°C to 50°C).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 15 minutes to 5 hours (more preferably from 30 minutes to 2 hours) will usually suffice.
  • the desired compound from each reaction can be recovered from the reaction mixture by conventional means.
  • one such method comprises: neutralising properly the reaction mixture; distilling off the solvent from the reaction mixture; or if necessary, after distilling off the solvent, pouring the reaction mixture into water; extracting the mixture with a water-immiscible organic solvent; and distilling off the solvent from the extract, to leave the desired product as a residue.
  • the resulting product can be further purified by conventional means, such as recrystallisation, reprecipitation or the various chromatography techniques, notably column chromatography.
  • a compound of formula (Ic) that is a compound of formula (I) wherein R2 represents a group of formula -B-S(O) m -R5 (wherein R5, B and m are as defined above), is prepared by reacting a compound of formula (VI) with a compound of formula (VII), normally in an inert solvent in the presence of a base and then, if desired, oxidising the resulting thioether compound.
  • bases which may be used for the reaction include: alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; alkali metal hydrogencarbonates, such as sodium hydrogencarbonate or potassium hydrogencarbonate; and organic amines, such as trimethylamine, triethylamine, pyridine, dimethylaniline, N -methylmorpholine or 4-( N , N -dimethylamino)pyridine. Of these, we prefer the alkali metal hydroxides.
  • the reaction is normally and preferably effected in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol or isopropanol; amides, such as dimethylformamide diethylformamide or dimethylacetamide; nitriles, such as acetonitrile; and sulphoxides, such as dimethyl sulphoxide. Of these, we prefer the alcohols.
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform
  • ethers such as diethyl ether, tetrahydrofuran or dio
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20°C to 100°C (more preferably from 0°C to 50°C).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 5 hours (more preferably from 30 minutes to 2 hours) will usually suffice.
  • Oxidation can be conducted by oxidising the corresponding thioether compound with an oxidising reagent in an inert solvent.
  • oxidising reagents which may be used for this reaction include: inorganic peroxides, such as hydrogen peroxide or periodic acid; peroxyaliphatic acids, such as peracetic acid or perpropionic acid; peroxyarylic acids, such as perbenzoic acid or m -chloroperbenzoic acid; and metal salts of peroxyphthalic acids, such as magnesium monoperoxyphthalate. Of these, we prefer the peroxyarylic acids.
  • the reaction is normally and preferably effected in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform; and ethers, such as diethyl ether, tetrahydrofuran or dioxane. Of these, we prefer the halogenated hydrocarbons.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -30°C to 50°C (more preferably from -20°C to room temperature).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 5 hours (more preferably from 30 minutes to 2 hours) will usually suffice.
  • a sulphinyl compound may be obtained by using about an equimolar of the oxidising reagent per mole of the thioether compound, and a sulphonyl compound may be obtained by using more than two moles of the oxidising reagent per mole of the thioether compound.
  • the corresponding acyloxyalkyl compound can be prepared by acylating the hydroxy group.
  • compounds of formula (Ic), wherein R5 represents: a C1-C5 alkanoyloxy group; a C2-C5 alkanoyloxy group substituted with a C2-C5 alkoxycarbonyl, C7-C11 aryloxycarbonyl or C6-C10 aryl group; a C7-C11 arylcarbonyloxy group; or an alkyl group substituted with a C3-C6 cycloalkylcarbonyloxy group, can be prepared by reacting a hydroxy compound with the corresponding carboxylic acid compound or with a reactive derivative thereof.
  • reaction conditions used in the reaction of the hydroxy compound with the carboxylic acid compound are similar to those used, in the presence of a condensing agent, in Reaction C, described above.
  • Reaction of the hydroxy compound with a reactive derivative of the carboxylic acid compound is preferably conducted in an inert solvent in the presence or absence of a base.
  • reactive derivative of the carboxylic acid used, provided that it is a compound capable of producing an ester compound by reaction with an alcohol compound, and it will, of course, depend on the nature of the group which it is desired to introduce.
  • reactive derivatives which may be used for the reaction include: acid halides, such as acetyl chloride, propionyl chloride, valeryl chloride, valeryl bromide, isovaleryl chloride, methyl chloroformylacetate, ethyl 3-chloroformylpropionate, ethyl 4-chloroformylbutyrate, ethyl 5-chloroformylvalerate, phenylacetyl chloride, phenylpropionyl chloride, benzoyl chloride, toluoyl chloride, naphthoyl chloride, cyclopropanecarbonyl chloride, cyclobutanecarbonyl chloride, cyclopentanecarbonyl chlor
  • any base may be used, provided that it has no adverse effect on any part of the molecule of the reagents.
  • preferred bases include: organic amines, such as trimethylamine, triethylamine, pyridine, dimethylaniline, N -methylmorpholine or 4-( N , N -dimethylamino)pyridine; and particularly preferably triethylamine or N -methylmorpholine. An excess of the organic amine can also serve as a solvent.
  • the reaction is normally and preferably effected in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; esters, such as ethyl acetate or propyl acetate; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and nitriles, such as acetonitrile.
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform
  • ethers such as diethyl ether, tetrahydrofuran or dioxane
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -10°C to 50°C (more preferably from 0°C to 30°C).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 24 hours will usually suffice.
  • R5 represents an alkyl group substituted with a carboxyl group
  • the corresponding compounds of formula (Ic) can be prepared by reacting a hydroxy compound with a cyclic carboxylic acid anhydride, such as succinic anhydride, glutaric anhydride or adipic anhydride (preferably succinic anhydride or glutaric anhydride).
  • a cyclic carboxylic acid anhydride such as succinic anhydride, glutaric anhydride or adipic anhydride (preferably succinic anhydride or glutaric anhydride).
  • the reaction is normally and preferably effected in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; amides, such as dimethylformamide, diethylformamide or dimethylacetamide; nitriles, such as acetonitrile; and sulphoxides, such as dimethyl sulphoxide. Of these, we prefer the ketones.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20°C to 100°C (more preferably from 0°C to 50°C).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 8 hours (more preferably from 1 to 5 hours) will usually suffice.
  • the carboxylic acid compounds obtained above may be converted to the corresponding ester compounds by conventional esterification procedures, including reacting the carboxylic acid compound with a diazo compound, such as diazomethane, diazoethane, diazopropane, diazobutane or trimethylsilyldiazomethane in an inert solvent (preferably an ether, such as diethyl ether, tetrahydrofuran or dioxane), at about room temperature for a period of from 10 minutes to 2 hours.
  • a diazo compound such as diazomethane, diazoethane, diazopropane, diazobutane or trimethylsilyldiazomethane
  • an inert solvent preferably an ether, such as diethyl ether, tetrahydrofuran or dioxane
  • the desired compound prepared in this step can be recovered from the reaction mixture by conventional means.
  • one such technique comprises: neutralising properly the reaction mixture; distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture, pouring the reaction mixture into water; extracting the mixture with a water-immiscible organic solvent; and finally distilling off the solvent from the extract.
  • the product can be purified by conventional means, for example, recrystallisation, reprecipitation or the various chromatography techniques, notably column chromatography.
  • Reaction E comprises an alternative method for preparing a compound of formula (Ic).
  • a compound of formula (Ic) is prepared by reacting a compound of formula (VIII) with a compound of formula (IX) and, if desired, oxidising the thioether compound thus obtained. This step is carried out in a similar manner as those described above in Reactions C and D.
  • a compound of formula (Id) that is, a compound of formula (I) wherein R2 represents a group of formula -CH2S(O) m (CH2) p +1OH (wherein m and p are as defined as above), is prepared by reacting a compound of formula (II) with a compound of formula (X), normally in an inert solvent.
  • the reaction is normally and preferably effected in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; ethers, such as diethyl ether, tetrahydrofuran or dioxane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; and alcohols, such as methanol, ethanol or isopropanol.
  • the reaction may also be carried out in the absence of a solvent.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20°C to 130°C (more preferably from 50°C to 100°C).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 5 hours (more preferably from 1 to 2 hours) will usually suffice.
  • the desired compound prepared in this step can be recovered from the reaction mixture by conventional means.
  • one such technique comprises: neutralising properly the reaction mixture; distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture, pouring the reaction mixture into water; extracting the mixture with a water-immiscible organic solvent; and finally distilling off the solvent from the extract.
  • the product can be purified by conventional means, for example, recrystallisation, reprecipitation or the various chromatography techniques, notably column chromatography.
  • a compound of formula (Ie) that is, a compound of formula (I) wherein R2 represents a group of formula -B-S(O) m -R 5a (wherein R 5a , B and m are as defined above), can be prepared by reacting a compound of formula (XI) with a reducing reagent in an inert solvent.
  • reducing reagents examples include: borohydride compounds, such as lithium borohydride, sodium borohydride, calcium borohydride or sodium cyanoborohydride. Of these, we prefer sodium borohydride.
  • the reaction is normally and preferably effected in the presence of a solvent.
  • a solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol or ethanol; water; or a mixture of any two or more of these solvents. Of these, we prefer a mixture of an alcohol and an ether.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20°C to 100°C (more preferably from 0°C to 30°C).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 1 to 24 hours (more preferably from 3 to 10 hours) will usually suffice.
  • the desired compound prepared in this step can be recovered from the reaction mixture by conventional means.
  • one such technique comprises: neutralising properly the reaction mixture; distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture, pouring the reaction mixture into water; extracting the mixture with a water-immiscible organic solvent; and finally distilling off the solvent from the extract.
  • the product can be purified by conventional means, for example, recrystallisation, reprecipitation or the various chromatography techniques, notably column chromatography.
  • the starting materials of formula (II) are known or can be prepared by any of several known methods (for example, as described Japanese Patent Kokai Application No. Sho 61-85365 or in an analogous manner).
  • the starting compounds of formulae (VI), (VIII) and (XI) can be prepared by reacting a compound of formula (II) with a compound of formula HOCO-B-X, HOCO-B-SY' or HOCO-B-SR6, in which: R6, B and X are as defined above; and Y1 represents a hydrogen atom, an alkali metal, a C2-C5 alkanoyl group (such as an acetyl, propionyl, butyryl or valeryl group, preferably an acetyl or propionyl group) or an aromatic acyl group in which the aromatic part has from 6 to 10 ring carbon atoms (such as a benzoyl, toluoyl or naphthoyl group, preferably a benzoyl group).
  • the compound produced may, if desired, be subjected to hydrolysis using a base (for example, an alkali metal alkoxide, such as sodium methoxide or sodium ethoxide, or an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide) at a temperature of from -20°C to 80°C (more preferably from 0°C to 50°C) in an inert solvent (for example, an alcohol, such as methanol or ethanol) for a suitable period, for example from 5 minutes to 10 hours (more preferably from 10 minutes to 5 hours) to give a compound in which Y' is a hydrogen atom.
  • a base for example, an alkali metal alkoxide, such as sodium methoxide or sodium ethoxide, or an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide
  • an inert solvent for example, an alcohol, such as methanol or ethanol
  • the pyridyloxy derivatives of the present invention have excellent histamine-H2 receptor antagonist activity, and are therefore useful for the prevention and therapy of peptic diseases resulting from undesirable peptic secretion, such as gastric ulcers, duodenal ulcers, gastritis, esophagistis, gastric dispepsia and Zollinger-Ellison syndrome; they are also useful for the prophylaxis or treatment of gastric disease before surgery.
  • the compounds of the present invention may be administered in any conventional form known for use with compounds having this type of activity, the precise form depending on the patient and the preferred route of administration, as is well known in the art.
  • oral administration they may be formulated as tablets, capsules, granules, powders or syrups; and for parentheral administration they may be formulated as injections.
  • the compounds of the present invention may be administered by themselves or in admixture with conventional additives, such as vehicles (for example lactose, mannitol, corn starch or crystalline cellulose), binders (for example cellulose derivatives, gum arabic or gelatin), disintegrating agents (for example calcium carboxymethylcellulose), lubricants (for example talc or magnesium stearate), stabilisers, corrigents, solvents for preparing injections (for example water, ethanol or glycerin).
  • vehicles for example lactose, mannitol, corn starch or crystalline cellulose
  • binders for example cellulose derivatives, gum arabic or gelatin
  • disintegrating agents for example calcium carboxymethylcellulose
  • lubricants for example talc or magnesium stearate
  • stabilisers for example corrigents
  • solvents for preparing injections for example water, ethanol or glycerin.
  • the dosage may vary depending on the age, condition and symptoms of the patient, as well as the nature and severity of the disorder being treated, however, the usual daily dosage for an adult human patient would be from 1 mg to 1000 mg (preferably from 10 mg to 500 mg), per day, which may be administered as a single dose or divided into several doses.
  • the activity of the compounds of the present invention is illustrated by the following Test Examples. In these, the compounds of the invention are identified by the number of the subsequent Example in which its preparation is illustrated. The prior art compounds A, B and C are as identified in the introductory portion of this specification.
  • the guinea pig right atrium in a spontaneous palpitation was excised, suspended in 40 ml of Krebs-Henselite solution, and a tension of 1 g was loaded between the atrium preparation and a transducer.
  • the solution was aerated at a fixed rate at 37°C. 10 ⁇ 5 M histamine was added, and the heart rate was recorded as control.
  • a test compound was added to a concentration of 1 ⁇ g/ml and then, after 3 minutes, 10 ⁇ 5 M histamine was added, and the heart rate was again recorded.
  • Table 5 Compound of Example No. Dose (mg/kg) % Inhibition 1 50 63 2 50 52 6 50 73 7 25 63 7 12.5 51 13 50 80 13 25 62 17 50 71 17 25 73 34 25 86 34 12.5 61 37 50 74 41 50 76 41 25 61 48 50 71 58 50 56 A 50 -67 B 50 -40 C 50 56
  • the hydrochloride of the title compound melting at 198 - 208°C, was prepared by dissolving the compound obtained above in ethyl acetate, after which it was treated with an excess of a 4 N ethyl acetate solution of hydrogen chloride.
  • the oxalate of the title compound melting at 127 - 133°C, was prepared by dissolving the title compound, obtained as described above, in acetone, after which an equimolar amount of oxalic acid was added, and crystals of the oxalate, which precipitated, were collected by filtration.
  • Infrared Absorption Spectrum (liquid film), ⁇ max cm ⁇ 1: 3298, 2935, 1647, 1613, 1560, 1421, 1403, 1311, 1301, 1289, 1070.
  • the extract was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography through silica gel, using a 1 : 19 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.39 g (yield 85%) of the title compound as an oil.
  • the hydrochloride of the title compound melting at 99 - 106°C, was prepared by dissolving the title compound, prepared as described above, in diethyl ether, after which the resulting solution was treated with an equimolar amount of a 4 N ethyl acetate solution of hydrogen chloride.
  • the dihydrochloride of the title compound melting at 235 - 255°C, was prepared by dissolving the title compound, prepared as described above, in ethyl acetate, after which the resulting solution was treated with a molar excess of a 4 N ethyl acetate solution of hydrogen chloride.
  • reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 100 : 5 : 2 by volume mixture of methylene chloride, triethylamine and methanol as the eluent, to give 0.49 g of the triethylamine salt of the title compound in an 80% yield.
  • the extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1 : 40 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.31 g of the title compound in a 61% yield.
  • the dihydrochloride of the title compound melting at 185 - 195°C, was prepared by dissolving the compound obtained above in ethyl acetate, after which the resulting solution was treated with a molar excess of a 4 N ethyl acetate solution of hydrogen chloride.
  • the reaction mixture was then stirred at room temperature for 1 hour, after which it was heated under reflux for 16 hours. At the end of this time, it was concentrated by evaporation under reduced pressure.
  • the concentrate was purified by column chromatography through silica gel, using a 1 : 9 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.18 g of the title compound in a 35% yield.
  • the reaction mixture was stirred at room temperature for 15 minutes, after which it was poured into ice-water and extracted with ethyl acetate.
  • the extract was concentrated by evaporation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 1 : 9 by volume mixture of methanol and methylene chloride as the eluent, to give 0.56 g of the title compound as an oil in a 65% yield.
  • the extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulphate.
  • the solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1 : 9 by volume mixture of methanol and chloroform as the eluent, to give 1.65 g (yield 51%) of the title compound as a white powder, melting at 121 - 123°C.
  • the extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulphate.
  • the solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1 : 19 by volume mixture of methanol and methylene chloride as the eluent, to give 499 mg (yield 73%) of the title compound as an oil.
  • the hydrochloride of the title compound melting at 180 - 183°C, was prepared by dissolving the title compound obtained above in ethyl acetate, after which it was treated with an equimolar amount of an ethyl acetate solution of hydrogen chloride.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 2-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colourless prisms, melting at 136 - 137°C, in an 80% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 1,3,5-trimethyl-4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 75 - 77°C, in a 69% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 3-amino-4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 172 - 174°C, in a 38% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 3-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 57% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 5-methyl-3-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 93 - 95°C, in a 52% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 5-methyl-2-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound, melting at 71 - 73°C, was obtained in a 72% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 3-amino-2-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colourless needles, melting at 138 - 140°C, in a 40% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 3-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 90% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 5-chloro-3-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colourless prisms, melting at 75 - 77°C, in a 54% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 5-phenyl-3-isoxazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound, melting at 105 - 106°C, was obtained as colourless prisms in a 50% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 4-thiazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 68% yield.
  • Infrared Absorption Spectrum (liquid film), ⁇ max cm ⁇ 1: 2936, 1664, 1611, 1560, 1540, 1481, 1420, 1403, 1313, 1288.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 1,2,3-thiadiazole-4-carboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colourless needles, melting at 70 - 72°C, in a 52% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]- cis -2-butenylamine and 4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 57 - 61°C, in a 34% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]- cis -2-butenylamine and 2-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 124 - 127°C, in a 64% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 1-methyl-2-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 76% yield.
  • the hydrochloride of the title compound melting at 136 - 137°C, was prepared by dissolving the title compound, obtained as described above, in ethyl acetate, after which an ethyl acetate solution containing an equimolar amount of hydrogen chloride was added to the resulting solution.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 3-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 74% yield.
  • the extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 9 : 1 by volume mixture of ethyl acetate and methanol as the eluent, to give 10.1 g (yield 92%) of the title compound as an oil.
  • Infrared Absorption Spectrum (liquid film), ⁇ max cm ⁇ 1: 3295, 2936, 1646, 1611, 1564, 1548, 1420, 1403, 1382, 1312, 1300, 1289.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and diphenylmethylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 69% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 1-methylpropylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 72 - 74°C, in an 80% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 1-methylbutylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 66% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 1-methylhexylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 65% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 1-phenylethylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 62% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 1-ethylpropylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 82 - 84°C, in a 77% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 1,2-dimethylpropylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 73% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 1,2-diphenylethylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 80% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and cyclopropylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 102 - 104°C, in a 60% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and cyclobutylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 130 - 132°C, in a 66% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and cyclopentylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 121 - 124°C, in a 77% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and cyclohexylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 131 - 132°C, in a 72% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and cycloheptylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 89 - 91°C, in a 60% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and cyclooctylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 59% yield.
  • Example 48 Following a procedure similar to that described in Example 48, but using 3-(4-piperidinomethyl-2-pyridyloxy)propylamine and isopropylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 58 - 60°C, in a 50% yield.
  • the extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulphate.
  • the solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1 : 9 by volume mixture of methanol and chloroform as the eluent, to give 1.2 g (yield 85%) of the title compound as a white powder, melting at 117 - 119°C.
  • Example 64 Following a procedure similar to that described in Example 64, but using 4-(4-piperidinomethyl-2-pyridyloxy)butylamine and 4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 145 - 147°C, in a 71% yield.
  • Example 64 Following a procedure similar to that described in Example 64, but using 5-(4-piperidinomethyl-2-pyridyloxy)pentylamine and 4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 105 - 106°C, in a 57% yield.
  • the extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1 : 9 by volume mixture of methanol and ethyl acetate as the eluent, to give 3.40 g (yield 87%) of the title compound as an oil.
  • the extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1 : 9 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.41 g (yield 75%) of the title compound as an oil.
  • the extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1 : 9 by volume mixture of methanol and methylene chloride as the eluent, to give 0.49 g (yield 88%) of the title compound as an oil.
  • Example 67(a) Following a procedure similar to that described in Example 67(a), but using 4-(4-piperidinomethyl-2-pyridyloxy)butylamine and 2-chloroacetyl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 59 - 63°C, in an 80% yield.
  • Example 68 Following a procedure similar to that described in Example 68, but using 5-(4-piperidinomethyl-2-pyridyloxy)pentylamine and 1,4-oxathian-2-one as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 78% yield.
  • Example 67(a) Following a procedure similar to that described in Example 67(a), but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 5-chlorovaleryl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 93% yield.
  • Example 67(a) Following a procedure similar to that described in Example 67(a), but using N -[4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 6-bromohexanoyl bromide as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 86% yield.
  • the extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1 : 19 by volume mixture of methanol and ethyl acetate as the eluent, to give 1.72 g (yield 77%) of the title compound as an oil.
  • Example 68 Following a procedure similar to that described in Example 68, but using 4-(4-dimethylaminomethyl-2-pyridyloxy)- cis -2-butenylamine and 1,4-oxathian-2-one as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 53% yield.
  • the reaction mixture was washed with a 10% w/v aqueous solution of sodium hydrogensulphite, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, and then the solvent was removed by distillation under reduced pressure.
  • the residue was purified by column chromatography through silica gel, using a 1 : 9 by volume mixture of ethanol and chloroform as the eluent, to give 0.40 g (yield 40%) of the title compound as an oil.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-dimethylaminomethyl-2-pyridyloxy)- cis -2-butenylamine and 4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 65% yield.
  • Example 13 Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenylamine and 3,5-dimethylpyrrole-2-carboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as crystals, melting 140 - 141°C, in a 58% yield.
  • Infrared Absorption Spectrum (liquid film), ⁇ max cm ⁇ 1: 3325, 2936, 1636, 1611, 1561, 1523, 1420, 1402, 1301, 1290, 1039.
  • the title compound prepared as described above, was dissolved in ethyl acetate and treated with an equimolar amount of a 4 N solution of hydrogen chloride in ethyl acetate to give the hydrochloride of the title compound, melting at 258 - 261°C (with decomposition).
  • Example 77 Following a procedure similar to that described in Example 77, but using N -[4-(4-piperidinomethyl-2-pyridyloxy)- cis -2-butenyl]-4-(2-pyrimidinylthio)butyramide (prepared as described in Example 34) as a starting material, in a relative proportion similar to that used in that Example, the title compound was obtained as an oil in a 55% yield.
  • Infrared Absorption Spectrum (liquid film), ⁇ max cm ⁇ 1: 3302, 2936, 1657, 1612, 1561, 1420, 1403, 1384, 1312, 1300, 1289, 1062, 1040, 753.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
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EP93302221A 1992-03-23 1993-03-23 Antimagengeschwür Pyridyloxyderivate, Verfahren zu deren Herstellung und ihre Verwendung Expired - Lifetime EP0562833B1 (de)

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EP0796847A1 (de) * 1996-03-18 1997-09-24 Shiseido Company Limited Pyridinderivate,als Arzneimittel zur Behandlung von Geschwüren und als antibakterielle Mittel

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IT1251474B (it) * 1991-09-13 1995-05-15 Mini Ricerca Scient Tecnolog Derivati ossimici ad attivita' fungicida

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EP0023578A1 (de) * 1979-07-03 1981-02-11 Shionogi & Co., Ltd. Aminoalkylbenzol-Derivate, Verfahren zu ihrer Herstellung und pharmazeutische Zusammensetzungen
JPS6185365A (ja) 1984-10-02 1986-04-30 Ikeda Mohandou:Kk アミノアルキルピリジルオキシ誘導体
EP0214823A2 (de) * 1985-08-29 1987-03-18 FUJIREBIO KABUSHIKI KAISHA also trading as FUJIREBIO INC. Alkylamidderivate mit H2-rezeptorantagonistischer und zytoprotektiver Aktivität
EP0282077A2 (de) 1987-03-13 1988-09-14 Fujirebio Kabushiki Kaisha Pyridyloxy-Derivate
JPS63225371A (ja) 1987-03-13 1988-09-20 Fujirebio Inc ピリジルオキシ誘導体
EP0302422A2 (de) * 1987-08-03 1989-02-08 Kyorin Pharmaceutical Co., Ltd. Harnstoff-Derivate
JPH01193247A (ja) 1988-01-29 1989-08-03 Fujirebio Inc ピリジルオキシ誘導体
WO1990000544A1 (en) 1988-07-05 1990-01-25 Zeria Pharmaceutical Co., Ltd. Substituted acetamide derivatives, process for their preparation and antiulcer drug containing same
JPH04257581A (ja) 1991-02-08 1992-09-11 Kyorin Pharmaceut Co Ltd ピペリジノメチルピリジン誘導体

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US4300549A (en) * 1980-01-07 1981-11-17 Surgikos Operating room face mask
JPH0193247A (ja) * 1987-10-05 1989-04-12 Toshiba Corp マルチノードシステム
DE69106172D1 (de) * 1990-03-06 1995-02-09 Akzo Nobel Nv Wässrige Hybridpolymerdispersion und Beschichtungszusammensetzung.

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EP0023578A1 (de) * 1979-07-03 1981-02-11 Shionogi & Co., Ltd. Aminoalkylbenzol-Derivate, Verfahren zu ihrer Herstellung und pharmazeutische Zusammensetzungen
JPS6185365A (ja) 1984-10-02 1986-04-30 Ikeda Mohandou:Kk アミノアルキルピリジルオキシ誘導体
EP0214823A2 (de) * 1985-08-29 1987-03-18 FUJIREBIO KABUSHIKI KAISHA also trading as FUJIREBIO INC. Alkylamidderivate mit H2-rezeptorantagonistischer und zytoprotektiver Aktivität
EP0282077A2 (de) 1987-03-13 1988-09-14 Fujirebio Kabushiki Kaisha Pyridyloxy-Derivate
JPS63225371A (ja) 1987-03-13 1988-09-20 Fujirebio Inc ピリジルオキシ誘導体
EP0302422A2 (de) * 1987-08-03 1989-02-08 Kyorin Pharmaceutical Co., Ltd. Harnstoff-Derivate
JPH01193247A (ja) 1988-01-29 1989-08-03 Fujirebio Inc ピリジルオキシ誘導体
WO1990000544A1 (en) 1988-07-05 1990-01-25 Zeria Pharmaceutical Co., Ltd. Substituted acetamide derivatives, process for their preparation and antiulcer drug containing same
EP0404949A1 (de) 1988-07-05 1991-01-02 Zeria Pharmaceutical Co., Ltd. Substituierte acetamid-derivate, verfahren zur herstellung und antigeschwulstheilmittel, das diese enthalten
JPH04257581A (ja) 1991-02-08 1992-09-11 Kyorin Pharmaceut Co Ltd ピペリジノメチルピリジン誘導体

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Publication number Priority date Publication date Assignee Title
EP0796847A1 (de) * 1996-03-18 1997-09-24 Shiseido Company Limited Pyridinderivate,als Arzneimittel zur Behandlung von Geschwüren und als antibakterielle Mittel

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NO931041L (no) 1993-09-24
HK159796A (en) 1996-08-30
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NO931041D0 (no) 1993-03-23
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US5616579A (en) 1997-04-01
HUT64053A (en) 1993-11-29
IL105140A0 (en) 1993-07-08
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DK0562833T3 (da) 1996-09-09
TW240222B (de) 1995-02-11
HU9300827D0 (en) 1993-06-28
CN1081437A (zh) 1994-02-02
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AU3537993A (en) 1993-09-30
GR3020069T3 (en) 1996-08-31

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